The present invention relates to fluorous phosphine compounds and to methods of increasing the fluorous nature of chemical entities using such fluorous phosphine compounds, and, particularly, to branched fluorous phosphine compounds and to methods of increasing the fluorous nature of chemical entities using such branched fluorous phosphine compounds.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
Fluorous techniques for the synthesis of small organic molecules are becoming increasingly useful as more and more fluorous compounds are synthesized and studied. These techniques are attractive for strategic separation of reaction mixtures since fluorous-tagged compounds can be quickly separated from non-tagged compounds in, for example, binary liquid-liquid and solid-liquid extractions. Fluorous tagging is discussed, for example, in U.S. Pat. Nos. 5,859,247, 5,777,121, and 6,156,896, and U.S. patent application Ser. No. 09/506,7796, all assigned to the assignee of the present invention, the disclosures of which are incorporated herein by reference. The fluorine content of a fluorous molecule is an important aspect to be balanced to obtain suitable performance during both the reaction and the separation. Opposing needs during reaction and separation can be thought of as dividing the fluorous field into two branches or techniques, which have recently been termed xe2x80x9cheavy fluorousxe2x80x9d and xe2x80x9clight fluorousxe2x80x9d. Those two techniques are actually ends of a continuum with a considerable gray area in between.
On the heavy fluorous end, fluorous techniques strive for very high partition coefficients in liquid-liquid separation, requiring fluorous reagents and catalysts with large numbers of fluorine atoms. Heavy fluorous techniques afford easy separation, but the large numbers of fluorines tend to render the fluorous compounds insoluble in typical organic reaction solvents. Fluorous cosolvents are thus used which have poor dissolving power for organic compounds, so the modification and optimization of reaction conditions is often required. However, once suitable conditions are found, the resulting heavy fluorous techniques are very powerful, especially when applied to catalytic reactions.
On the light fluorous end, the number of fluorine atoms are reduced to provide fluorous compounds that have properties more similar to their organic parents. While reduction of the fluorine content can allow the use of standard literature reaction conditions with little or no modification, the reduced fluorine content compromises the separation of fluorous from non-fluorous components by liquid-liquid extraction. However, the recently introduced technique of fluorous solid phase extraction is proving far superior to liquid-liquid extractions for separation of compounds with fewer fluorines. See, for example, a) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714. b) Curran, D. P.; Luo, Z. Y. J. Am. Chem. Soc. 1999, 121, 9069. c) Curran, D. P.; Hadida, S.; Kim, S. Y.; Luo, Z. Y. J. Am. Chem. Soc. 1999, 121, 6607. d) Curran, D. P.; Hadida, S.; Studer, A.; He, M.; Kim, S. -Y.; Luo, Z.; Larhed, M.; Hallberg, M.; Linclau, B. In Combinatorial Chemistry: A Practical Approach; H. Fenniri, Ed.; Oxford Univ Press: Oxford, in press; Vol. 2. Light fluorous techniques are especially useful for small scale and discovery oriented research, including parallel synthesis applications and so-called techniques of fluorous synthesis. See, for example, a) Curran, D. P. Med. Res. Rev. 1999, 19, 432; b) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823. c) Curran, D. P. The Cancer Journal 1998, 4 Supp. 1, S73.
Fluorous biphasic catalysis (FBC) was the original fluorous technique introduced in 1994 by Horvxc3xa1th and Rxc3xa1bai, and that technique is finding increasing utility in the catalysis community. Horvxc3xa1th, I. T.; Rxc3xa1bai, J. Science 1994, 266, 72. Most of the work in the area of fluorous biphasic catalysis involves the use of fluorous phosphines and phosphites. Mathivet, T.; Monflier, E.; Castanet, Y.; Mortreux, A.; Couturier, J. L. Tetrahedron Lett. 1999, 40, 3885. The original trialkylphosphine ligand [P(CH2CH2C6F13)3] introduced by Horvxc3xa1th and Rxc3xa1bai has proved useful in a number of reactions catalyzed by rhodium and iridium. See, for example, a) Guillevic, M. A.; Rocaboy, C.; Arif, A. M.; Horvxc3xa1th, I. T.; Gladysz, J. A. Organometallics 1998, 17, 707. b) Horvxc3xa1th, I. T.; Kiss, G.; Cook, R. A.; Bond, J. E.; Stevens, P. A.; Rabai, J.; Mozeleski, E. J. J. Am. Chem. Soc. 1998, 120, 3133. c) Juliette, J. J. J.; Rutherford, D.; Horvxc3xa1th, I. T.; Gladysz, J. A. J. Am. Chem. Soc. 1999, 121, 2696. d) Li, C. B.; Nolan, S. P.; Horvxc3xa1th, I. T. Organometallics 1998, 17, 452. e) Smith, D. C.; Stevens, E. D.; Nolan, S. P. Inorg. Chem. 1999, 38, 5277.
More recently, a number of fluorous analogs of triphenylphosphine have appeared, and several of these are shown in FIG. 1. Phosphine 1a was introduced by Leitner for reactions in supercritical carbon dioxide and has also found use in an FBC variant of the popular palladium catalyzed allylic substitution (Tsuji/Trost) reaction. Kainz, S.; Koch, D.; Baumann, W.; Leitner, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1628; Kling, R.; Sinou, D.; Pozzi, G.; Choplin, A.; Quignard, F.; Busch, S.; Kainz, S.; Koch, D.; Leitner, W. Tetrahedron Lett. 1998, 39, 9439. Related phosphine 2a, lacking the ethylene spacer, has been used by Knochel as a ligand for palladium catalyzed Negishi couplings and Heck reactions. Betzemeier, B.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 2623. Hope and coworkers have prepared families of phosphines bearing one, two, and three fluorous chains in both the para (2a-c) and meta (3a-c) series and studied the properties of several organometallic complexes of these ligands. See, a) Fawcett, J.; Hope, E. G.; Kemmitt, R. D. W.; Paige, D. R.; Russell, D. R.; Stuart, A. M.; ColeHamilton, D. J.; Payne, M. J. Chem. Commun. 1997, 1127. b) Bhattacharyya, P.; Gudmunsen, D.; Hope, E. G.; Kemmitt, R. D. W.; Paige, D. R.; Stuart, A. M. J. Chem. Soc., Perkin Trans. 1 1997, 3609. c) Fawcett, J.; Hope, E. G.; Kemmitt, R. D. W.; Paige, D. R.; Russell, D. R.; Stuart, A. M. J. Chem. Soc. Dalton Trans. 1998, 3751. d) Hope, E. G.; Kemmitt, R. D. W.; Stuart, A. M. J. Chem. Soc. Dalton Trans. 1998, 3765. e) Sinou, D.; Pozzi, G.; Hope, E. G.; Stuart, A. M. Tetrahedron Lett. 1999, 40, 849. f) Hope, E. G.; Kemmitt, R. D. W.; Paige, D. R.; Stuart, A. M.; Wood, D. R. W. Polyhedron 1999,18, 2913. g) Hope, E. G.; Kemmitt, R. D. W.; Paige, D. R.; Stuart, A. M. J. Fluorine Chem. 1999, 99, 197. Ligands with a silyl spacer (see 4a) have been synthesized and studied by van Koten and coworkers. See, for example, a) Richter, B.; Deelman, B. J.; van Koten, G. J. Mol. Catal. A Chem. 1999, 145, 317. b) Richter, B.; Spek, A. L.; vanKoten, G.; Deelman, B. J. J. Am. Chem. Soc. 2000, 122, 3945. c) Richter, B.; deWolf, E.; vanKoten, G.; Deelman, B. J. J. Org. Chem. 2000, 65, 3885. d) deWolf, E.; Richter, B.; vanKoten, G.; Deelman, B. J. J. Org. Chem. 2000, 65, 5424.
Given the utility of recently developed fluorous techniques, it is highly desirable to develop additional fluorous compounds that can be used in such techniques.
In one aspect, the present invention provides a method of increasing the fluorous nature of a compound. The method includes the step of reacting the compound with or tagging the compound with at least one of a second compound having the formula: 
wherein R is an alkyl group or an aryl group, n is 1, 2 or 3 and Rs is a spacer group and Rf is a branched fluorous group.
In another aspect, the present invention provides a chemical compound having the general formula: 
wherein n, Rs and Rf are defined above.
Spacer groups suitable for use in the present invention preferably act to neutralize, reduce or compensate for the electron withdrawing effect of the fluorous group Rf. Rs can, for example, be an C1-C12 alkylene group or (xe2x80x94CH2xe2x80x94)x wherein x is 1-12. More preferably, Rs is a C1-C6 alkylene group.
The terms xe2x80x9calkylxe2x80x9d, xe2x80x9carylxe2x80x9d and other groups as used herein refer generally to both unsubstituted and substituted groups unless specified to the contrary. Unless otherwise specified, alkyl groups are hydrocarbon groups and are preferably C1-C15 (that is, having 1 to 15 carbon atoms) alkyl groups, and more preferably C1-C10 alkyl groups, and most preferably C1-C6, and can be branched or unbranched, acyclic or cyclic. The above definition of an alkyl group and other definitions apply also when the group is a substituent on another group. The term xe2x80x9carylxe2x80x9d refers generally to phenyl (Ph) or napthyl, substituted or unsubstituted. Alkyl groups can, for example, be substituted with one or more groups including, but not limited to, a halogen, an alkoxy group and/or, an aryl group. Aryl groups can, for example, be substituted with one or more groups including, but not limited to, a halogen, an alkoxy group and/or an alkyl group. The term xe2x80x9calkoxy groupxe2x80x9d as used herein refers generally to xe2x80x94OR, wherein R is an alkyl group.
As used herein, the term xe2x80x9cfluorousxe2x80x9d, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, hydrofluoroalkyl groups and perfluoroalkyl groups). As used herein, the term xe2x80x9cperfluoroalkyl groupsxe2x80x9d refers generally to alkyl groups in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms xe2x80x9cfluorohydroalkyl groupsxe2x80x9d and xe2x80x9chydrofluoroalkyl groupsxe2x80x9d include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. Flourous group Rf preferably has a molecular weight in the range of approximately 200 to approximately 1000. More preferably, Rf has a molecular weight in the range of approximately 200 to approximately 550.
The term xe2x80x9cbranchedxe2x80x9d as use herein in connection with hydrofluoroalkyl groups and perfluoroalkyl groups refers generally to a group that has at least one carbon atom attached to at least three other carbon atoms. The branched hydrofluoroalkyl groups and perfluoroalkyl groups of the present invention can be cyclic or acyclic. The branched fluorous groups of the present invention preferably have no Cxe2x80x94H bonds xcex2 to a carbon-fluorine (Cxe2x80x94F) bond to eliminate the possibility of HF elimination reaction of the tag under strongly basic conditions. An example of a Cxe2x80x94H bond xcex2 to a Cxe2x80x94F bond is provided below. 
In several embodiments in which Rs is an alkylene group, Rf is branched at the carbon atom adjacent Rs such that there is no Cxe2x80x94H bond in Rs that is xcex2 to a Cxe2x80x94F bond. Such branched fluorous groups for use in the present invention include, but are not limited to, xe2x80x94C(CF3)2C3F7 and xe2x80x94C(CF3)2C4F9 or generally, xe2x80x94CRf1Rf2(CF2Rf3) wherein Rf1, Rf2 and Rf3 are independently (the same or different) a fluorous group (preferably, a hydrofluoroalkyl group or a perfluoroalkyl group). Rf1 and Rf2 can also form a hydrofluoroalkyl ring or a perfluoroalkyl ring of 3 to 12 members (preferably, 5 to 6 members). Alternatively, Rf1 and Rf3 can form a hydrofluoroalkyl ring or a perfluoroalkyl ring of 3 to 12 members (preferably, 5 to 6 members). Likewise, Rf2 and Rf3 can form a hydrofluoroalkyl ring or a perfluoroalkyl ring of 3 to 12 members (preferably, 5 to 6 members). In the case of xe2x80x94C(CF3)2C3F7, Rf1 is xe2x80x94CF3, Rf2 is xe2x80x94CF3 and Rf3 is xe2x80x94C2F5.
As used herein, the term xe2x80x9ctaggingxe2x80x9d refers generally to attaching a fluorous moiety or group (referred to as a xe2x80x9cfluorous tagging moietyxe2x80x9d or xe2x80x9ctagging groupxe2x80x9d) to a compound to create a xe2x80x9cfluorous tagged compoundxe2x80x9d. Separation of the tagged compounds of the present invention can be achieved by using fluorous separation techniques that are based upon differences between/among the fluorous nature of a mixture of compounds. As used herein, the term xe2x80x9cfluorous separation techniquexe2x80x9d refers generally to a method that is used to separate mixtures containing fluorous molecules or organic molecules bearing fluorous domains or tags from each other and/or from non-fluorous compounds based predominantly on differences in the fluorous nature of molecules (for example, size and/or structure of a fluorous molecule or domain or the absence thereof). Fluorous separation techniques include but are not limited chromatography over solid fluorous phases such as fluorocarbon bonded phases or fluorinated polymers. See, for example, Danielson, N. D. et al., xe2x80x9cFluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,xe2x80x9d J. Chromat., 544, 187-199 (1991). Examples of suitable fluorocarbon bonded phases include commercial Fluofix(copyright) and Fluophase(trademark) columns available from Keystone Scientific, Inc. (Bellefonte, Pa.), and FluoroSep(trademark)-RP-Octyl from ES Industries (Berlin, N.J.). Other fluorous separation techniques include solid-liquid (or solid phase) extraction and liquid-liquid based separation methods such as liquid-liquid extraction or countercurrent distribution with a fluorous solvent and an organic solvent.
The compounds of the present invention are particularly suitable for creating fluorous metal ligands. In that regard, the present invention also provides metal complexes of a metal and at least one phosphine and/or phosphine oxide as described above. The metal is preferably rhodium, platinum, paladium, nickel, iron, ruthenium, osmium, cobalt or iridium.
In still a further aspect, the present invention provides a method of synthesizing a branched fluorous phosphine comprising the steps of: reacting a fluoroalkene with a metal fluoride; adding an alkylating agent to produce a fluorous halo arene; converting the fluorous halo arene to an organometallic derivative thereof; and reacting the organometallic derivative with R3xe2x88x92nP(Z3)n wherein Z3 is a leaving group and wherein R is an alkyl group or an aryl group.